高血压引起的病理性心肌肥厚（PCH）是引起心衰和心律失常的重要原因。心脏负荷增加后激活β肾上腺素能受体（βAR)信号，但是，βAR在PCH中的作用还不完全清楚。我们的前期工作发现，βAR激活PKA可被内源PKA抑制肽PKIα调节，高血压引起PKIα表达减低；当PKA在小鼠心脏特异性地被抑制后,高血压不能诱导PCH；在培养的新生大鼠心肌细胞，PKA抑制肽PKIα1-25过表达抑制α和βAR激动剂、血管紧张素II、内皮素等引起的心肌细胞肥大，其机理可能是通过抑制蛋白合成达到的。因此，我们假设βAR激活的PKA通过调节GSK3, AMPK 和Akt而激活mTORC1蛋白合成信号，该步骤是心肌肥大的必须环节。我们将利用PKIα敲除小鼠和PKIα1-25-GFP转基因小鼠研究PKIα及PKA在心肌肥大中的蛋白翻译作用机理，探索利用PKA抑制作为防治心肌肥大的新的手段。

Pathological cardiac hypertrophy (PCH) due to high blood pressure is a signficant contributor for heart failure and arrhythmias. When the haert is stressed, the β-adrenergic receptor（AR) signaling is activated.However, the role of the βAR signaling in PCH is not fully studied. Our preliminary studies have shown that βAR-induced PKA activity in the cardiomyocyte can be regulated by endogenous PKIα,pressure-overload caused a decrease in PKIαexpression; when PKA was inhibited by PKIα1-25 in a cardiac specific manner in mice, high blood pressure could not induce PCH; in cultured neonatal rat ventricular myocytes, PKIα1-25-GFP inhibited myocyte hypertrophy induced byα-and β-adrenergic agonists, angiotensin II, and endothelin could not induced myocyte hypertrophy, the udnerlying mechanism could be due to protein synthesis inhibition by PKIα1-25. Therefore, we hypothesize that β-AR activation leads to the activation of PKA which enhances protein synthesis through regulating GSK3, AMPK and Akt and their downstream mTORC1 signaling； this step is required for cardiac hypertrophy. We will use our newly developed PKIα knockout and PKIα1-25-GFP transgenic mice to study how PKIαand PKA regulates protein synthesis during cardiac hypertrophy, eventually explore the potential of using cardiac PKA inhibiton as a novel way of PCH prevention and treatment.